With an increasing number of elderly people, there have been proposed various compounds having therapeutic and/or prophylactic actions on senile dementia. Among these compounds, there has been found a therapeutic/prophylactic action in physostigmine, a naturally-occurring cholinesterase inhibitor (International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 29, No.1, p.23-37(1991) etc.). Physostigmine has, however, such defects as a relatively short duration of the action and high toxicity.
On the other hand, various heterocyclic compounds have been suggested as synthetic medicines. For example, EP-A-0,378,207, U.S. Pat. No. 4,849,431 corresponding to JPA-62(1987)-234065, U.S. Pat. No. 4,895,841 corresponding to JPA-64(1989)-79151, JPA-2(1990)-169569 and EP-A-0,468,187 disclose cholinesterase inhibitors having nitrogen-containing heterocyclic ring (hereinafter referred to as N-containing heterocyclic ring). U.S. Pat. No. 4,064,255 corresponding to JPA-52(1977)-72829 and U.S. Pat. No. 4,208,417 corresponding to JPA-55(1980)-9070 respectively disclose heterocyclic compounds used as an antidepressant or antianxiety drugs.
More particularly, EP-A-0,378,207 discloses a cyclic amino compound of the following formula or salts thereof: ##STR2##
wherein B stands for an optionally substituted saturated or unsaturated 5- to 7-membered azaheterocylic group; A represents a bond, an alkylene group or an alkenylene group which may be substituted with a hydrocarbon residue, an oxo group or hydroxyl group; {character pullout}represents a single bond or double bond (provided that A represents a bond, {character pullout}represents a single bond); R.sub.2 and R.sub.3 independently represent a hydrogen atom or an optionally substituted hydrocarbon residue (provided that they are not H at the same time) or may form a cyclic amino group taken together with the adjacent nitrogen atom; n denotes 0, 1 or 2; and p notes 1 or 2, or salts thereof. PA1 R.sup.1 represents a monovalent group derived from a member selected from optionally substituted benzene, pyridine, pyrazine, indole, anthraquinone, quinoline, optionally substituted phthalimide, homophtalimide, pyridine carboxylimide, pyridine-N-oxide, pyrazine carboxylimide, naphthalenedicarboxylimide, optionally substituted quinazolinedione, 1,8-naphthalimide, bicyclo[2.2.2]oct-5-ene-2,3-dicarboxylimide and pyromellylimide; PA1 X represents a group of the formula --(CH.sub.2).sub.m -- (wherein m denotes an integer of 0 to 7); a group of the formula --O(CH.sub.2).sub.n --; a group of the formula --S(CH.sub.2).sub.n --; a group of the formula --NH(CH.sub.2).sub.n --; a group of the formula --SO.sub.2 NH (CH.sub.2).sub.n --; a group of the formula --NH--CO--(CH.sub.2).sub.n --; a group of the formula --NH(CH.sub.2).sub.n --CO--; a group of the formula --COO(CH.sub.2).sub.n --; a group of the formula --CH.sub.2 NH(CH.sub.2).sub.n --; a group of the formula --CO--NR.sup.3 --(CH.sub.2).sub.n --(in the definition of X, in all formula, n each denotes an integer of 0 to 7; and R.sup.3 represents a lower alkyl group or benzyl group); a group of the formula --O--CH.sub.2 CH.sub.2 CH(CH.sub.3)--; a group of the formula --O--CH(CH.sub.3)CH.sub.2 CH.sub.2 --; a group of the formula --O--CH.sub.2 CH.sub.2 CH.dbd.; or a group of the formula --O--CH.sub.2 CH(OH)CH.sub.2 --; Ring A represents a group of the formula ##STR5## PA1 a group of the formula ##STR6## PA1 a group of the formula ##STR7## PA1 a group of the formula ##STR8## PA1 R.sup.2 represents a hydrogen atom, a lower alkyl group, an optionally substituted benzyl group, optionally substituted benzoyl group, pyridyl group, 2-hydroxyethyl group, pyridylmethyl group or group of the formula: ##STR9## PA1 J represents PA1 B represents a group of the formula --(C(R.sup.2)H).sub.n --; a group of the formula --CO--C(R.sup.2)H).sub.n --; a group of the formula --NR.sup.2 --(C(R.sup.2)H).sub.n -- (wherein R.sup.2 represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, an optionally substituted phenyl group or benzyl group); a group of the formula --CO--NR.sup.4 --C(R.sup.2)H).sub.n -- (wherein R.sup.4 represents a hydrogen atom, a lower alkyl group or a phenyl group), a group of the formula --CH.dbd.CH--(C(R.sup.2)H).sub.n --; a group of the formula --O--COO--(C(R.sup.2)H).sub.n --; a group of the formula --O--CO--NH--(C(R.sup.2)H).sub.n --; a group of the formula --NH--CO--(C(R.sup.2)H).sub.n --; a group of the formula --CH.sub.2 --CO--NH--(C(R.sup.2)H).sub.n --; a group of the formula --CO--NH--(C(R.sup.2)H).sub.n --; a group of the formula --C(OH)H--(C(R.sup.2)H).sub.n -- (in the above formulae, n denotes 0 or an integer of 1 to 10, R.sup.2 represents a hydrogen atom or a methyl group in the form of an alkylene group of the formula --(C(R.sup.2)H).sub.n -- which is unsubstituted or having one or more than one methyl group); a group of the formula.dbd.(CH--CH.dbd.CH).sub.b -- (wherein b denotes an integer of 1 to 3); a group of the formula.dbd.CH--(CH.sub.2).sub.c -- (wherein c denotes 0 or an integer of 1 to 9); a group of the formula.dbd.(CH--CH).sub.d.dbd. (wherein d denotes 0 or an integer of 1 to 5); a group of the formula.dbd.CO--CH.dbd.CH--CH.sub.2 --; a group of the formula --CO--CH.sub.2 --C(OH)H--CH.sub.2 --; a group of the formula --C(CH.sub.3)H--CO--NH--CH.sub.2 --; a group of the formula --CH.dbd.CH--CO--NH--(CH.sub.2).sub.2 --; a group of the formula --NH--; a group of the formula --O--; a group of the formula --S--; a dialkylaminoalkylcarbonyl group or a lower alkoxycarbonyl group; PA1 T represents a nitrogen atom or a carbon atom; PA1 Q represents a nitrogen atom, a carbon atom or a group of the formula &gt;N.fwdarw.O; PA1 K represents a hydrogen atom, an optionally substituted phenyl group, an arylalkyl group optionally substituted with a phenyl group, a cinnamyl group optionally substituted with phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantanemethyl group, a furylmethyl group, a cycloalkyl group, a lower alkoxycarbonyl group or an acyl group; q denotes an integer of 1 to 3 .dbd. and represents a single bond or a double bond, and a cholinesterase inhibitor containing the above mentioned compounds. PA1 wherein R.sup.1 represents a group derived from an optionally substituted cyclic amide compound; n denotes an integer of 0 to 10; and Z represents a formula: ##STR14## PA1 wherein R represents a hydrogen atom, a C.sub.1-4 alkyl group or a aralkyl group having 1 or 2 carbon atom(s) in the alkyl moiety thereof; X represents a hydrogen atom or a halogen atom, an alkyl, an alkoxy or an alkylthio group each optionally having 1 to 4 carbon atoms, trifluoromethyl, nitro, hydroxy or unsubstituted amino group, or an amino group substituted with one or two alkyl, acyl or alkylsulfonyl group; A represents a group --CO--, or a group --CH.sub.2 --; and n represents 0, 1 or 2. PA1 wherein R is a hydrogen atom, a C.sub.1-4 alkyl group or an aralkyl group whose alkyl moiety has 1 or 2 carbon atoms; X is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group whose alkyl moiety has 1 to 4 carbon atoms; A sands for --CO-- or --CH.sub.2 --; and n denotes 1 or 2. PA1 wherein m denotes 0 to 3; n denotes 0 to 3; m and n are not 0 simultaneously; p denotes 0 to 3; X represents O, S, SO, SO.sub.2, NR.sup.6, CR.sup.7 R.sup.8, CO or CHOH; R.sup.1, R.sup.3 and R.sup.7 each represents a hydrogen atom, a C.sub.1-5 alkyl group, a halogen atom, a group of the formula NR.sup.10 R.sup.11, OH, COOH, a C.sub.2-6 alkoxycarbonyl group, CN, Ar, a C.sub.1-5 alkoxy group or a C.sub.1-5 alkylthio group; R.sup.2, R.sup.4 and R.sup.8 each represents a hydrogen atom, a C.sub.1-5 alkyl group, a C.sub.2-6 alkoxycarbonyl, CN, a C.sub.1-5 alkoxy group or Ar.sup.1 ; when X is O, S, SO, SO.sub.2 or NR.sup.6, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are not a C.sub.1-5 alkoxy, a C.sub.1-5 alkylthio, the group NR.sup.10 R.sup.11 or OH; R.sup.5 represents a hydrogen atom, an alkyl group, a halogen atom, OH or an alkenyl group; R.sup.6 represents a hydrogen atom, a C.sub.1-5 alkyl group or Ar.sup.1 ; Ar and Ar.sup.1 each represents a naphthyl group, a pyridyl group, a pyrimidyl group, an indolyl group, a quinolinyl group, an isoquinolinyl group or a phenyl group, and these groups being optionally substituted with a C.sub.1-3 alkyl group, a C.sub.1-3 alkoxy group, a C.sub.1-3 haloalkyl group having 1 to 7 halogen atoms, SH, a S(O).sub.t --C.sub.1-3 alkyl group (wherein t denotes 1, 2 or 3), a C.sub.2-6 dialkylamino group, a halogen atom, a C.sub.1-3 alkylamino group, NH.sub.2, CN, NO.sub.2, SO.sub.3 H, a tetrazole group, COOH, a C.sub.2-6 alkoxycarbonyl, CONH.sub.2, SO.sub.2 NO.sub.2, COR.sup.9, CONR.sup.12 R.sup.13, SO.sub.2 NR.sup.12 R.sup.13, Ar.sup.2, OAr.sup.2 or SAr.sup.2 ; Ar.sup.2 represents a naphthyl or a phenyl group, and these groups optionally substituted with a C.sub.1-3 alkyl group, a C.sub.1-3 haloalkyl group having 1 to 7 halogen atoms, a C.sub.1-3 alkoxy group, a halogen atom or a C.sub.1-3 alkylthio group; R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 each represents a halogen atom, a C.sub.1-5 alkyl group or a phenyl group, R.sup.10 and R.sup.11 may, taken together, form a C.sub.3-6 alkylene chain and R.sup.12 and R.sup.13 may, taken together, form a C.sub.3-6 alkylene chain; a or b represents a single bond or double bond, both are not simultaneously a double bond. PA1 wherein R is Ac, COEt, COPr, COCHMe.sub.2, CO(CH.sub.2).sub.2 Cl, CO(CH.sub.2).sub.3 Cl, COCH.sub.2 NMe.sub.2, CO(CH.sub.2).sub.2 NMe.sub.2, CO(CH.sub.2).sub.3 NMe.sub.2, and salts thereof or R is COCH.dbd.CHPh; X is CH.sub.2, or O; and n is 1, 2 or 3 (wherein Ac represents an acetyl group; Et, Pr and Me represent a ethyl group, a propyl group, a methyl group respectively; and Ph represents a phenyl group). PA1 wherein R.sup.1 is H or Me; n is 2 or 3. PA1 wherein R.sup.1 is H or Me; R.sup.2 is H, Cl or Me; R.sup.3 is H, F, Me, OMe or Cl; n is 1, 2 or 3; Z is O, OH or H (for compound I) or R.sup.2 is H or Cl; R.sup.4 is H or Me; NR.sup.5.sub.2 is NMe.sub.2, morpholino or piperidino (for compound II). PA1 wherein R is a 4-cycloalkylphenyl group, 3,4-methylenedioxyphenyl group, 2,3-dihydro-5-benzofuranyl group; R.sup.1 is an alkyl group, a cycloalkyl group or a cyclopentylmethyl group; R.sup.2 is an optionally substituted pyrrolidino, piperidino, hexahydro-1H-azepine-1-yl or octahydro-1-azocinyl group. PA1 wherein R is H or Me. PA1 wherein R.sup.1 is an alkyl group or a phenyl group; R.sup.2 is a C.sub.1-3 alkyl group; R.sup.3 is an alkenyl group, an alkynyl group, a cycloalkyl group or an alkyl group; R.sup.4 is H or an alkyl group; NR.sup.3 R.sup.4 is a morpholino group, a pyrrolidino group or a piperidino group; R.sup.5 is H or a C.sub.1-3 alkyl group; R.sup.6 is H or an acyl group; n is 1 to 3; X is S, O or NH; and Y is CH.sub.2 or S, as an intermediate product of aminoalchol derivatives of the following formula, which has a depressing action, an antispasmodic action, a vasodilating action and a calmative action: ##STR27## PA1 wherein R.sup.1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atom(s); R.sup.2 shows a C.sub.1-3 alkyl group; ##STR29## PA1 n denotes an integer of 1 to 5. PA1 wherein ring A is an optionally substituted benzene ring; ring B' is an optionally substituted non-aromatic heterocyclic ring having, the same or different, two or more hetero atoms; R.sup.1 is a hydrogen atom or an optionally substituted hydrocarbon group, which may be different from one another in the repetition of n; Y is an optionally substituted amino group or an optionally substituted N-containing saturated heterocyclic group; n denotes an integer of 1 to 10, provided that when ring B' is a 5- to 7-membered ring, ring B' contains at least one nitrogen atom as hetero atoms and n denotes an integer of 2 to 10, or a salt thereof. PA1 wherein ring A, ring B' R.sup.1 and n have the same meanings as defined above; and Z.sup.2 represents a leaving group, or a salt thereof. PA1 wherein ring A and ring B' are as defined above, or a salt thereof, with a compound of the formula: ##STR38## PA1 wherein R.sup.2 and R.sup.3 are, the same or different, H, an optionally substituted hydrocarbon group or an optionally substituted acyl group, and R.sup.2 and R.sup.3 may form an optionally substituted N-containing saturated heterocyclic group; and ring A, ring B', R.sup.1 and n are as defined above, or a salt thereof, PA1 which comprises reacting a compound of the formula: ##STR40## PA1 wherein ring A is an optionally substituted benzene ring; ring B is an optionally substituted non-aromatic heterocyclic ring having independently two or more hetero atoms; R.sup.1 is a hydrogen atom or an optionally substituted hydrocarbon group, which may be different from one another in the repetition of n; Y is an optionally substituted amino group or an optionally substituted N-containing saturated heterocyclic group, n denotes an integer of 1 to 10, or a salt thereof. PA1 wherein R.sup.6 represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted acyl group. PA1 wherein R.sup.2' and R.sup.3' represent, respectively, a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted acyl group. PA1 wherein ring Q.sup.1 represents a 5- to 9-membered N-containing saturated heterocyclic group which may have, other than carbon atoms and one nitrogen atom, 1 to 2 hetero atoms selected from nitrogen, oxygen, sulfur atoms and so on. Practical examples of these rings are shown as follows: ##STR51## PA1 wherein ring Q.sup.2 represents a 5- to 9-membered N-containing saturated heterocyclic group which may have, other than carbon atoms and one nitrogen atom, 1 or 2 of nitrogen, oxygen, sulfur atoms, etc. as hetero atoms. As typical examples of these rings, there may be mentioned: ##STR53## PA1 wherein R.sup.6 represents a hydrogen atom, an optionally substituted C.sub.7-10 aralkyl group, or an optionally substituted acyl group, which may be substituted with an oxo group. PA1 wherein Ac represents an acetyl group; Et represents an ethyl group; and Ph represents a phenyl group. PA1 wherein Z.sup.1 represents a leaving group and other symbols have the same meanings as defined above, or a salt thereof. PA1 wherein each symbol has the same meaning as defined above, or a salt thereof, with a compound represented by the formula: ##STR574## PA1 wherein R.sup.4 and R.sup.5 each represents a hydrogen atom or an optionally substituted hydrocarbon group, and other symbols have the same meanings as defined above, or a salt thereof, can be produced also by reacting, for example, a compound of the formula: ##STR577## PA1 wherein each symbol has the same meaning as defined above,or a salt thereof. PA1 wherein Z.sup.5 represents a leaving group, and other symbols have the same meanings as described above. PA1 wherein R.sup.7 represents an optionally substituted hydrocarbon group; and Z.sup.3 represents a leaving group.
Practically it discloses a compound of the following formula among others: ##STR3##
In U.S. Pat. No. 4,849,431 corresponding to JPA-62(1987)-234065, there are disclosed piperidine derivatives of the following formula or pharmaceutically acceptable salts thereof: ##STR4##
wherein
(wherein Z represents a halogen atom). PA2 (a) optionally substituted groups shown as follows; (1) a phenyl group, (2) a pyridyl group, (3) a pyrazyl group, (4) a quinolyl group, (5) a cyclohexyl group, (6) a quinoxalyl group or (7) a furyl group, PA2 (b) a mono- or di-valent group selected from the following groups which may be substituted on the phenyl group; (1) an indanyl group, (2) an indanonyl group, (3) an indenyl group, (4) an indenonyl group, (5) an indandionyl group, (6) a tetranonyl group, (7) a benzsperonyl group, (8) an indanolyl group or (9) a group of the formula: ##STR12## PA2 (c) a monovalent group derived from a cyclic amide compound, PA2 (d) a lower alkyl group or PA2 (e) a group of the formula R.sup.1 --CH.dbd.CH-- (wherein R.sup.1 represents a hydrogen atom or a lower alkoxycarbonyl group); PA2 wherein R.sup.2 represents an aryl group, a substituted aryl group, a cycloalkyl group or a heterocyclic group; m denotes an integer of 1 to 6; R.sup.3 represents a hydrogen atom or a lower alkyl group; R.sup.4 represents an aryl group, a substituted aryl group, a cycloalky group or a heterocyclic group; p denotes an integer of 1 to 6, provided that when the cyclic amide compound is quinazolinone or quinazolinedione derivative, R.sup.2 and R.sup.4 are neither an aryl group nor a substituted aryl group. PA2 wherein Y represents a hydrogen atom, --OCH.sub.3, a halogen atom or ##STR30## PA2 wherein Z.sup.1 is a leaving group; R.sup.1, Y and n are as defined above, or a salt thereof. PA2 wherein Z.sup.2 is a leaving group; ring A, ring B', R.sup.1 and n are as defined above, or a salt thereof, with a compound of the formula: ##STR41## PA2 wherein Z.sup.4 represents a leaving group, and other symbols have the same meanings as defined above. PA2 wherein each symbol has the same meaning as defined above, or a salt thereof, with a compound represented by the formula: EQU R.sup.5 --CHO [XI]
Practically, there is disclosed a compounds of the following formula among them: ##STR10##
U.S. Pat. No. 4,895,841 corresponding to JPA-64(1989)-79151, and JPA-2(1990)-169569 disclose a cyclic amine derivative of the following general formula or pharmaceutically acceptable salts thereof: ##STR11##
wherein
A practical embodiment thereof is the following compound. ##STR13##
EP-A-0,468,187 discloses a cyclic amide compound of the formula: EQU R.sup.1 --(CH.sub.2).sub.n --Z
Practically, it discloses a compound of the following formula among them: ##STR15##
U.S. Pat. No. 4,064,255 corresponding to JPA-52(1977)-72829 discloses a pharmaceutical composition used for treatment of pathological conditions caused by disturbances in serotonin systems, which comprises a compound of the formula or pharmaceutically acceptable salts thereof: ##STR16##
U.S. Pat. No. 4,208,417 corresponding to JPA-55(1980)-9070 discloses medicinally active compounds having an affinity for the binding site of .sup.3 H-diazepam which are indole derivatives having the general formula: ##STR17##
Further, WO91/03243 discloses a compound, which is used as a psychopharmaceutical, of the following general formula or pharmaceutically acceptable salts thereof: ##STR18##
Furthermore, various condensed heterocyclic derivatives containing a hetero atom such as a nitrogen, an oxygen, a sulfur atom and the like have been suggested and their biological activity and pharmacological actions have been reported. Cholinesterase inhibitory action and actions as therapeutic/prophylactic agents of senile dementia, however, have not been disclosed therein.
More definitely, Chem. Abstr., 107, 190332h(1987) discloses that a compound of the following general formula has an anti-inflammatory action: ##STR19##
Chem. Abstr., 89, 36594y(1978) discloses that the compound of the general formula has an antispasmic action, depressing action of arterial blood pressure and a local anesthetic action: ##STR20##
Journal of Pharmacology, 97, 540(1977) discloses that a compound of the following general formula has an antidepressant action: ##STR21##
EP-163,537 discloses that a compound of the general formula has a muscular relaxant action: ##STR22##
Chem. Abstr., 91,211631y (1979) discloses that a compound of the following formula is synthesized as a derivative of cystisine, which is an alkaloid having an anticholinergic action: ##STR23##
Helvetica Chimica Acta, 51, 1616(1968) discloses compounds of the following formula (A) and (B): ##STR24##
as an intermediate products for synthesizing alkanolamines of the following formula (C), which is an agent acting on the sympathetic nervous system: ##STR25##
JPA-52(1977)-97952 discloses a compound of the formula: ##STR26##
wherein each symbol has the same meaning as defined above.
In JPA-59(1984)-7185 there is disclosed that a 1,5-benzoxepine derivative of the following formula or acid adducts thereof has a depressing action of blood pressure: ##STR28##
Chem. Abstr., 70, 106531j (1969) corresponding to FR-M3,635 discloses, for example, a compound of the formula: ##STR31##
as an intermediate product of 1,4-benzodioxane derivatives of the formula: ##STR32##
which is an agent acting on the sympathetic nervous system.
Further, Chem. Abstr., 67, 54087k (1967), 68, 105121x (1968), 75, 88548s (1971), 76, 153682t (1972) disclose methods for preparing 1,4-benzoxane derivatives of the formula: ##STR33##
wherein ##STR34##
represents an optionally substituted amino group or a cyclic amino group, and p denotes 1 or 2.
However, in these literatures, there is no disclosure of biological activity, pharmacological action and the like.